Reactive Oxygen Species (ROS) have been proposed to cause oxidative damage to biological molecules and to be involved in the development of many severe human disorders i.e., atherosclerosis, cancer, rheumatoid artritis and inflammation [Halliwell, B., and Gunteridge, J. M. C. (eds.) (1989) Free Radical in Biology and Medicine, Clarendon Press, London. Neuzil, J., et al. (1993) Biochem. J. 293:601-606; Sies, H., (ed.) (1985) Oxidative stress, Academic Press, London: Steinberg, D. et al. (1989) New Engl. J. Med. 320:915-923].
The antioxidants defense system is composed of several lines of defense. These lines of defense include macromolecular molecules (mainly enzymes such as superoxide dismutase (SOD), catalase glutathione peroxidase and other protecting enzymes) and low molecular weight antioxidants [Halliwell. B. (1990) Free Rad. Res. Comm. 9:1-327].
Despite intensive clinical trials using antioxidants, only marginal therapeutic and preventive successes have been reported [Rice-Evance. C. A., and Diplock A. T. (1993) Free Radical Biology & Medicine 15:77-96]. There are several reasons for the limited success in the use of antioxidants therapy:
1) Antioxidants can be classified according to their partition between aqueous and lipid compartments (lipoproteins and membranes) [Dean. R. T. et al. (1991) Free Radical Biology &, Medicine 11:161-168; Niki. E. et al. (1984) J. Biol. Chem. 259:4177-4182]. Most of the natural antioxidants cannot cross biological membranes and cannot move freely by spontaneous diffusion between aqueous and lipid environments. Some of them are ionized at natural physiologic pH, a fact that also restricts their movement. PA1 2) Antioxidants should not have any pro-oxidative effects, i.e. thiols group produced superoxide radicals causing LDL oxidation and NO. radical distraction or ascorbic acid that induced free radical production when coupled with a transition metal [Heinecke, J. et al. (1993) J. Lipid Res. 34:2051-2061; Jackson, R. L., et al. (1993) Medicinal Research Reviews 13:161-182; Ingold, K. U., et al. (1993) Proc. Natl. Acad. Sci. USA 90:45-49]; PA1 3) Halliwell (ibid.) clarified that essential antioxidants should possess a broad spectrum of ROS scavenging capacities and should be in close proximity to the biological target and at relatively high concentrations.
N,N'-dimethyl thiourea (DMTU) is a well known antioxidant and a potent hydroxyl radical scavenger, also capable of removing hydrogen peroxide and superoxide radicals [Kelner. M. J., et al. (1990) J. Biol. Chem. 265:1306-1311; Dey, G. R., et al. (1994) J. Chem. Soc. Perkin Trans 2:1625-1629]. Notwithstanding their antioxidative properties, various DMTU-derived compounds are relatively highly toxic (e.g., lung, liver and thyroid toxicity) and considered carcinogenic substances.
Thus, antioxidants which can fulfill the requirements mentioned above may serve as efficient molecules capable of coping with oxidative stress and may thus be good candidates for antioxidative therapy. There is a basic need for better antioxidants in order to prevent the tissues natural deterioration and to prevent inflammatory and other tissue damage caused by reactive oxygen species.
The present invention thus relates to novel compounds which are efficient, non-toxic, therapeutic antioxidants.